Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus

Abstract

Aims/hypothesis

The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM.

Methods

Female CD4-cre ERαfl/fl (KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERαfl/fl (ERα-floxed [FL]) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated.

Results

KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively; p < 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively; p < 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%; p < 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of Emr1 and Tnfa in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively; p < 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines, Ahsg and Fgf21 (both were 2.4-fold higher vs FL-GDM mice; p < 0.05 and p = 0.09, respectively), with no changes in inflammatory gene expression (e.g., Tnfa and Ifng) in the liver compared with FL-GDM mice.

Conclusions/interpretation

Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.

Graphical abstract

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Data availability

Data presented in this manuscript are available upon request from the corresponding authors.

Abbreviations

7AAD:

7-amino-actinomycin D

BV421:

Brilliant Violet 421

Cy7:

Cyanine7

ERα:

Oestrogen receptor α

FOXP3:

Forkhead box P 3

FL:

ERα-floxed (mice)

FL-GDM:

Pregnant ERαfl/fl (mice)

GDM:

Gestational diabetes mellitus

gWAT:

Gonadal white adipose tissue

HFD :

High-fat diet

KO:

CD4-cre ERαfl/fl (mice)

KO-GDM:

Pregnant CD4-cre ERαfl/fl (mice)

NK:

Natural killer

NPC:

Nonparenchymal cells

PE:

Phycoerythrin

SVF:

Stromal-vascular fraction

Th:

T helper

Treg:

Regulatory T cell

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Acknowledgements

The authors thank: P. Chambon (Institute for Genetics and Cellular and Molecular Biology, University of Strasbourg, Strasbourg, France) and Y. Imai (Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Ehime, Japan) for providing ERα-floxed mice; T. So (Department of Molecular Cell Biology, University of Toyama, Toyama, Japan) and M. Hamaguchi (Department of Endocrinology and Metabolism, Kyoto Prefectural University, Kyoto, Japan) for their technical advice regarding experiments with immunology and flow cytometry; K. Dezaki (Iryo Sosei University, Fukushima, Japan) for the technical advice regarding isolation of pancreatic islet; and T. Matsushima (Department of Pathology, University of Toyama, Toyama, Japan) for technical assistance with immunohistochemistry. Some of the data were presented as abstracts at the 56th EASD Annual Meeting and the 72nd Annual Congress of the Japan Society of Obstetrics and Gynecology in 2020.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

The present study was funded by the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Numbers JP15K09410, JP15K15599, JP18K08469, JP19H05011 and JP19K08997), a Grant for Research Activities of the First Bank of Toyama Scholarship Foundation, and a research grant from Mitsubishi Tanabe Pharma Corporation.

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TT helped design the study, performed experiments, analysed the data and wrote the manuscript; TW conceived and designed the study, performed experiments, analysed the data and wrote the manuscript; KU, SO, HI, and AO performed experiments and analysed the data; AI, TI, and YM performed experiments; AS, YO, MS, and AN analysed and interpreted the data; HT analysed and interpreted the data and edited the manuscript; SS helped design the study and critically reviewed the manuscript; TS supervise the study, analysed and interpretation of data, critically reviewed and edited the manuscript. All the authors have critically contributed to the revision of the article on important intellectual content. All the authors have approved the final version of this manuscript. TW and TS are the guarantors of this work.

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Correspondence to Tsutomu Wada.

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Tanaka, T., Wada, T., Uno, K. et al. Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05447-x

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Keywords

  • Gestational diabetes mellites
  • Hepatokines
  • Insulin secretion
  • Interleukin 17
  • Maternal beta cell adaptation
  • Oestrogen receptor α
  • Pancreatic islet
  • Th17
  • Treg